KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results

Abstract

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-ALL. We report the phase 1 results. Following fludarabine/cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2, 1, or 0.5×106 cells/kg. The rate of dose-limiting toxicities (DLTs) within 28 days following KTE-X19 infusion was the primary endpoint. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age: 46 years [range, 18-77]). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 31% and 38% of patients, respectively. To optimize the benefit-risk ratio, revised adverse event (AE) management for CRS and NE (earlier steroid use for NE and tocilizumab only for CRS) was evaluated at 1×106 cells/kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NE, with no grade 4/5 NE. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1×106 cells/kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At 22.1 months (range, 7.1-36.1) median follow-up, the median duration of remission was 17.6 months (95% CI, 5.8-17.6) in patients treated with 1×106 cells/kg and 14.5 months (95% CI, 5.8-18.1) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1×106 cells/kg with revised AE management.

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

“…The TNFR co-stimulatory domains were used based on their ability to maintain engraftment of the CAR T cells compared with CD28 co-stimulation domains 8,9 . The CD19 CAR incorporates an OX40 co-stimulatory domain and the CD22 CAR incorporates a 41BB domain (Fig.…”

Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies

“…It is likely that the short-term use of corticosteroids is practicable [161]. Moreover, the earlier administration of corticosteroids is under investigation [145,[162][163][164]. The ZUMA-3 trial administered corticosteroids at grade 2 ICANS after CD19 CAR T-cell therapy [162].…”

“…Moreover, the earlier administration of corticosteroids is under investigation [145,[162][163][164]. The ZUMA-3 trial administered corticosteroids at grade 2 ICANS after CD19 CAR T-cell therapy [162]. Compared with administering corticosteroids at grade 3 ICANS, there were significant reductions in the incidence rates of severe ICANS (11% vs 64%) and peak levels of cytokines and other proinflammatory markers in the early intervention group; CAR T-cell expansion was similar between the two groups [162].…”

Bibliometric Analysis of Chimeric Antigen Receptor-Based Immunotherapy in Cancers From 2001 to 2021

“…Of note, some journals ranked first on both lists, indicating that they might act as leaders and advocates to advance the research on this topic. Blood , the most popular co-cited journal and the journal with the highest IF among the top 10 most productive sources, was the pioneer publishing original research on CAR-T cell therapy in hematopoietic malignancy science at the very beginning of this field ( 27 ) and continued to publish novel research on CAR-based immunotherapy ( 28 ).…”